A Better Way to Measure MS Disability?

Objective gait parameters and an MRI myelin assay gain traction.

Action Points

These studies were published as abstracts and presented at a national meeting. The data and conclusions should be considered as preliminary until published in a peer reviewed journal.

Kinect-based postural control assessment is fast and feasible and appears to be a reliable tool to measure postural control with a simple stance test for patients with multiple sclerosis who show higher postural instability than healthy controls.

Clinicians and researchers have been growing increasingly unhappy with standard measures of disability in multiple sclerosis patients. The most common, the Expanded Disability Status Scale (EDSS), is considered insensitive and emphasizes certain aspects of function over others that may be just as important for patients. Two presentations at the recent European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting, held jointly this year with its North American counterpart, ACTRIMS, are examples of where the field may be headed.

Measuring Walk in MS, Cheaply and Efficiently

Researchers often rely on either visual inspection or motion capturing technology to determine how well a patient is walking. But the former is often inaccurate, and the latter can be expensive, said Jacob Sosnoff, PhD, of the University of Illinois in Urbana-Champaign, in a presentation at ECTRIMS-ACTRIMS.

Pressure sensitive walkways and motion tracking devices, however, can provide reliable and quantitative measures of ambulation in multiple sclerosis patients. Sosnoff and colleagues analyzed the walk of 86 ambulatory patients 6 months apart using GAITRite, a portable walkway sensitive to pressure. GAITRite -- whose products sell for $25,000 to $35,000 depending on the model, according to the company -- has previously been tested. In the current study, the researchers evaluated its reliability -- that is, whether results are similar in multiple tests during which the person's actual performance would not have changed substantially -- using intraclass correlation coefficients (ICC), which range from -1 to the perfectly correlated 1.

Five measures of walking were found to be reliable using the system:

Gait velocity: 0.94, 95% CI .84-.97

Functional ambulation profile: 0.94, 95% CI 0.90-0.96

Cadence: 0.94, 95% CI 0.83-0.97

Step time: 0.94, 95% CI 0.91-0.97

Double support: 0.75, 95% CI 0.60-0.85

"Ultimately, the goal is to help people," Sosnoff told MedPage Today. "And what was unique about this study is that we were using a time period of 6 months, which is how often someone would go to their neurologist or physical therapist." There was no intervention in between those 6 months, he said.

Of the patients in Sosnoff's study, 77% were female, and the median age was 50 (range 27 to 60). All of them had MS for at least 6 months, and 78% reported relapsing remitting MS. They had a self-reported disability of 3 on the patient determined disease steps scale (0-6). Patients were asked to walk 4.9 meters at their own pace on the GAITRite.

Walking impairment was reported as a primary limitation by 85% of study participants, said Sosnoff. "We want to target gait in rehabilitation, but, obviously, for us to target that, we need to have valid and reliable measures."

Currently, functional abilities in MS patients are most often assessed with the Expanded Disability Status Scale (EDSS), a categorical measure that relies on subjective evaluations that may vary between raters and is insensitive to small changes.

A continuous measure that is less subjective and that can be relied on to show genuine decreases or increases in functional ability over time would be useful both for clinical research and for routine patient management.

In a separate study, researchers used Microsoft Kinect -- a motion-sensing input device designed mainly for home video gaming -- to perform a postural control assessment. The $200 device was found to be reliable in measuring the impairment of MS patients using short stance tests, said Sebastian Mertens, a medical student at the NeuroCure Clinical Research Center-Charité in Berlin, Germany.

Mertens and his colleagues performed a cross-sectional study comparing 100 patients with MS with 60 healthy controls. The speed of three types of movements -- pitch, roll, and 3D -- was measured and compared with the EDSS, a timed 25-foot walk (T25W), a short maximum speed walk test (SMSW), and the WALK-12 evaluation. Participants did an open stance, a closed stance, and a tandem stance (i.e., with one foot in front of the other).

Participants in the study performed the test once with closed eyes and once with open eyes. ICC values for the three movements were 0.927, 0.900, and 0.943, respectively, with eyes closed, and 0.968, 0.933, and 0.971, respectively, with eyes open. In the closed stance, the 3D speed correlated modestly with the other measures:

EDSS: 0.458 (P<0.001, eyes open) and 0.531 (P<0.001, eyes closed)

SMSW: -0.332 (P<0.001) and no correlation with closed eyes

T25W: 0.318 (P<0.01, eyes open) and 0.331 (P<0.001, eyes closed)

WALK12: 0.340 (P<0.001, eyes open) and 0.478 (P<0.001, eyes closed)

Obvious impairment was observed in 30% of the MS patients, who also showed values outside the 99th percentile in the test with eyes closed.

There were no significant correlations with a patient's age, height, or body mass index. In the closed stance, MS patients were also found to have higher compensatory arm movements with eyes closed (P=0.001) and open (P=0.013) than in the control group.

"Kinect-based postural control assessment is fast and feasible," the researchers concluded.

Myelin Measure in MS Tracks Patient Disability

Whole-brain measures of myelin water fraction (MWF) -- reflecting the amount of myelin present in brain tissue -- correlated significantly with disease duration and disability levels in multiple sclerosis, supporting a role for MWF in patient management and as an outcome in clinical trials.

In a cross-sectional study of 141 MS patients and 10 neurologically healthy controls, the "skew" of one of two peaks seen in the distribution of MWF across the brain, including normal-appearing white matter as well in MS-type lesions, was associated with Expanded Disability Status Scale (EDSS) score (P=0.000039) and with the number of years since symptom onset (P=0.012), said Elizabeth Monohan, of Weill Cornell Medical College in New York City.

"To date, our study is the first to demonstrate an approach to modeling white matter myelin water fraction to explore clinical variables that may be driving myelin content," she said in a presentation at ECTRIMS-ACTRIMS.

"These observations promote the use of myelin water fraction as a biomarker for myelin," she added, noting that the relationship between MWF on the one hand and EDSS and disease duration on the other suggests that "myelin loss is accumulated during the disease and perhaps contributes to the progressive nature of MS."

Demyelination is the chief pathology in MS and is believed to be the driving force behind the physical disabilities that mark the disease in its later stages. Nerve fibers are sheathed in a protective layer of proteins dominated by myelin; its progressive loss leaves nerve axons vulnerable to various insults such that they eventually they break down, leading to loss of nerve function.

However, this process has been impossible to witness or measure directly in human patients. Recently, MWF -- measurable with MRI scans as the amount of water within myelin versus the total amount of water in the tissue scanned -- has emerged as a quantitative marker of myelin that can be assessed noninvasively in living patients.

Up till now, though, its clinical applicability has been uncertain, Monohan explained, because it was unclear whether focusing on MWF in lesioned areas was sufficient and also because the scans took a long time to perform and data analysis was difficult.

She said her group had developed a more practical approach to the scans that cut the image acquisition time to just 10 minutes for the whole brain. Moreover, she and her colleagues determined that scanning the whole brain was the right way to go, because there was no solid evidence to indicate that the clinically relevant demyelination occurs only in lesions.

An important finding in the study was that patients showed a "bimodal" distribution in histograms of MWF values -- a small spike in relatively low values and another larger spike in mid-range values. Monohan said that 94% of the patients showed this type of pattern, compared with just one of the 10 controls.

It was the shape of this spike in low values -- primarily the skew, but also its width -- that was most strongly correlated with EDSS and disease duration, she reported. The shape of the larger mid-value spike was associated with EDSS score but not disease duration.

Monohan said her group is pursuing additional studies to look at a broader patient population, with a wider range of EDSS scores and disease durations. Another goal is to examine MWF in patients undergoing treatment with current MS drugs.

Also, longitudinal studies to track within-patient changes in MWF over time will be necessary to determine how it may correlate with lesion evolution and, importantly, disease progression.

Sosnoff and colleagues disclosed no relevant relationships with industry.

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